Biomedical subjects

D R Anderson

Publications and source records attributed to D R Anderson.

At least 145 records · Page 8Linked to original sources

PubMed1992

Reduction by pyridostigmine pretreatment of the efficacy of atropine and 2-PAM treatment of sarin and VX poisoning in rodents.

This study concerned the effect of pyridostigmine pretreatment on (a) the antidotal efficacy of atropine and 2-PAM in sarin, tabun, and VX poisoning in mice and guinea pigs and on (b) the oxime-induced reactivation of VX-inhibited whole blood acetylcholinesterase (AChE) of guinea pigs. One hour prior to organophosphate (OP) challenge with sarin, tabun, or VX, animals were given oral doses of pyridostigmine to induce approximately 30 and 60% inhibition of whole blood AChE; controls received vehicle. Mice were challenged im and guinea pigs sc with the OP compounds. Treatment with atropine (11.2 mg/kg to mice; 32 mg/kg to guinea pigs) plus 2-PAM (25 mg/kg) was given im at 10 sec postchallenge in mice and 1 min postchallenge in guinea pigs. In the reactivation experiments, pyridostigmine or saline was given im to guinea pigs 30 min prior to VX (8.24 micrograms/kg, sc), atropine (16 mg/kg) was given im at 1 min, and 2-PAM (25 mg/kg) at 16 min postchallenge. Pyridostigmine significantly enhanced the efficacy of atropine and 2-PAM against tabun in both species. In contrast, pyridostigmine reduced or did not increase the efficacy of atropine and 2-PAM against sarin or VX in both species. Recovery of VX-inhibited AChE by 2-PAM was decreased significantly in pyridostigmine pretreated animals. The results suggest that pyridostigmine pretreatment may adversely effect the efficacy of atropine and 2-PAM as antidotes for VX and sarin intoxication.

Acetylcholinesterase↗

PubMed1992

Idiotype network responses to murine immunoglobulin G3 anti-carbohydrate antibodies.

Two murine monoclonal antibodies, 8A6 and 8C2, were generated against the carbohydrate moiety of tumor-associated disialoganglioside. Both of the antibodies were of the immunoglobulin G3 (IgG3), K isotype subclass. One of these antibodies (8A6) was used as a network immunogen for the generation of anti-idiotype antibodies. Two AB2 anti-idiotype antibodies were identified. One AB2 (12E5) was subsequently shown to recognize a linear epitope of the 8A6 kappa light chain. The second AB2 (9H8), recognizes a conformational epitope which is dependent on the maintenance of the tertiary structure of the idiotype. Both anti-idiotypes were injected into (syngeneic) mice and (xenogeneic) rabbits to evaluate their effectiveness as "network" antigens in promoting AB3 and anti-carbohydrate AB1' responses. AB3 populations from both syngeneic and xenogeneic hosts were found to be idiotype-specific, yet were unable to produce a measurable subpopulation of anti-tumor (AB1'). These studies suggest that IgG3 isotypes may not be suitable idiotype templates for the mimicry of carbohydrate epitopes.

Animals↗

PubMed1992

Screw fixation in the human sacrum. An in vitro study of the biomechanics of fixation.

A load-to-failure test was used to study the biomechanical properties of sacral screw fixation in human cadaveric specimens. The goals of this study were 1) to determine the effects of the two commonly chosen sacral screw orientations of fixation characteristics; 2) to determine the effects of selected screw-instrumentation linkages on the biomechanics of sacral screw fixation; 3) to correlate the biomechanical properties with a noninvasive assessment of sacral bone density; and 4) to correlate the torque during screw insertion with these biomechanical properties. The bone density of each specimen was measured with quantitative computed tomography. A screw was inserted from the dorsal surface either anteromedially or anterolaterally into the body of S1, and the torque needed to insert each screw was measured. The screw head was attached to a constrained or semiconstrained loading linkage. Force was applied to the screw in an inferior direction until the maximum load was achieved. The maximum load, screw translation, rotation at maximum load, and initial compliance of the bone-screw interface were determined. It was found that the anteromedial screw orientation, combined with a rigidly constrained loading linkage, resulted in the greatest maximum load to failure, the least screw rotation, and the least initial compliance of the four groups studied. The maximum load and the initial stiffness of bone-screw fixation increased significantly with bone density. Torque measurements correlated significantly with maximum load to failure, initial interface stiffness, and bone density. It was therefore concluded that bone density and torque measurements can be useful in assessing sacral screw fixation.

Aged↗

PubMed1992

Warfarin-induced skin necrosis in 2 patients with protein S deficiency: successful reinstatement of warfarin therapy.

Warfarin-induced skin necrosis is a rare but serious complication of oral anticoagulant therapy. This condition has been associated with protein C deficiency but only rarely reported in patients with a deficiency of protein S. We have managed 2 patients with a history of warfarin-induced skin necrosis who were diagnosed as being protein-S-deficient. Since both patients were candidates for long-term anticoagulant therapy we elected to reintroduce warfarin using a regimen designed to minimize the risk of recurrent skin necrosis. While they were therapeutically anticoagulated with heparin, warfarin was started at 1 mg/day and the dose was increased gradually. Heparin was not discontinued until the prothrombin times were in the therapeutic range for at least 72 h. Both patients tolerated the reinstitution of warfarin without difficulty and they have now been followed for over 2 years on oral anticoagulants without complication.

Adult↗

PubMed1992

Use of the accelerating rotarod for assessment of motor performance decrement induced by potential anticonvulsant compounds in nerve agent poisoning.

The accelerating rotarod was used to assess motor performance decrement in rats after administration of candidate anticonvulsant compounds (acetazolamide, amitriptyline, chlordiazepoxide, diazepam, diazepam-lysine, lorazepam, loprazolam, midazolam, phenobarbital and scopolamine) against nerve agent poisoning. All compounds were tested as the commercially available injectable preparation except for diazepam-lysine and loprazolam, which are not FDA approved. A peak effect time, as well as a dose to decrease performance time by 50% from control (PDD50), was determined. The calculated PDD50 (mumol/kg) values and peak effect times were midazolam, 1.16 at 15 min; loprazolam, 1.17 at 15 min; diazepam-lysine, 4.17 at 30 min; lorazepam, 4.98 at 15 min; diazepam, 5.27 at 15 min; phenobarbital, 101.49 at 45 min; chlordiazepoxide, 159.21 at 30 min; scopolamine, amitriptyline and acetazolamide did not demonstrate a performance decrement at any of the doses tested. The PDD50 values were compared with doses which have been utilized against nerve agent-induced convulsions or published ED50 values from standard anticonvulsant screening tests (maximal electroshock [MES] and subcutaneous pentylenetetrazol [scMET]). The results suggest that at anticonvulsant doses against nerve agents, all the benzodiazepines and phenobarbital have the potential to cause a performance decrement, whereas candidate anticonvulsants of the non-benzodiazepine or non-barbiturate type would not be expected to demonstrate this effect on motor performance. It is concluded that compounds such as acetazolamide, amitriptyline and scopolamine offer alternatives to the highly decrementing benzodiazepines and phenobarbital and should be further tested as anticonvulsant candidates against nerve agent intoxication.

Acetazolamide↗

PubMed1992

Successful pretreatment/therapy of soman, sarin and VX intoxication.

Chemical pretreatment is effective against a 2 LD50 challenge of soman, sarin or VX or a 5 LD50 challenge of tabun. Chemical pretreatment followed by post challenge therapy should be effective against greater levels of agent. Such tests in guinea pigs are reported here; pretreatment regimens (PRGs) consisted of physostigmine (0.15 mg/kg, im) and an adjunct. The adjuncts [mg/kg, im] used were aprophen [8], atropine (AT)[16], azaprophen (AZA)[5], benactyzine [1.25], benztropine (BT) [4], scopolamine [0.08] and trihexyphenidyl [2]. Pretreatment was given 30 min before, and atropine (16 mg/kg, im) and 2-PAM (25 mg/kg, im) therapy (T) at one min after, 5 LD50s of agent. Results indicate that, all of the PRG+T regimens, except BT-not tested with T, prevent lethality by soman; trihexyphenidyl and scopolamine (the only adjuncts used therein) regimens each prevent lethality by sarin and VX. Against soman, all PRG+T regimens (vs PRG only) may shorten the median recovery time to 2 hrs or less. Even without therapy, the PRGs containing AT, AZA or BT prevent lethality by 5 LD50s of soman; however, used alone, only the PRG containing AZA reduces the incidence of convulsions at this level of soman.

Animals↗

PubMed1992

The effect of pyridostigmine pretreatment on oxime efficacy against intoxication by soman or VX in rats.

This study was done to assess the effects of pyridostigmine (PYR) on a) the accumulation of labelled VX and soman within the brain, b) the therapeutic efficacy of atropine and oxime (2-PAM or HI-6) against intoxication by VX and soman and c) oxime-induced reactivation of inhibited acetylcholinesterase (AChE). In all experiments, rats were given PYR (131 micrograms/kg, im; I70 dose for whole blood AChE) or vehicle 30 min prior to nerve agent. In estimating 3H-agent the accumulation in the brain or estimating blood AChE activity, sufficient soman (47 micrograms/kg, iv) or VX (21.3 micrograms/kg, iv) was given to inhibit 50% of brain AChE activity. In assessing therapeutic efficacy and oxime-induced reactivation of blood AChE, rats were pretreated with PYR, challenged with agent and treated with atropine (16 mg/kg, im) and HI-6 or 2-PAM (100 umoles/kg, im) 30 sec post agent. Whole blood was collected by tail bleeding to monitor peripheral AChE activity at various time points before and after PYR and challenge. Pyridostigmine failed to alter covalent binding of labelled VX or soman in the brain. The 24-hr survival data showed that PYR reduced the therapeutic benefit of atropine and oxime against VX intoxication (but not soman). Protective ratios in VX-challenged rats given vehicle or PYR and treated with atropine + 2-PAM decreased slightly from 2.5 to 2.1 (p > .05), whereas with atropine + HI-6 they decreased significantly from 3.8 to 2.4. Also, AChE reactivation by HI-6 in VX-challenged rats was greater (p < .05) in vehicle- than in PYR-pretreated rats. HI-6 significantly reactivated AChE activity in both pretreatment groups (PYR or vehicle) given soman. The data suggest that PYR decreases the overall recovery of inhibited AChE in VX-challenged rats given HI-6; under the conditions used, this adverse effect decreases atropine+oxime efficacy against VX-induced lethality.

Animals↗

PubMed1992

Acetylcholinesterase inhibition and anti-soman efficacy of homologs of physostigmine.

Inhibition of acetylcholinesterase (AChE) activity by physostigmine (PHY) is reversible due to spontaneous decarbamylation. Physostigmine has been shown to be effective as a pretreatment against potent anticholinesterase poisons (e.g., soman) in experimental animals, yet it is short acting and causes undesirable side effects in mammals. The two-fold purpose of this study was 1) to determine whether extension of the N-substituted alkyl chain (N-SAC) of PHY from N-methyl to N-ethyl (I), N-propyl (II), N-isopropyl (III), N-butyl (IV) or N-heptyl (V) affects anti-AChE potency and spontaneous decarbamylation of inhibited AChE of guinea pig blood in vitro and in vivo, and 2) to see whether chain extension affects efficacy as pretreatment in poisoning by soman. The in vitro AChE inhibition studies were done using whole blood incubated at 37 degrees C for 30 min. All 5 homologs possessed anti-AChE activity with I50s ranging from 1.1 to 27.6 x 10(-7)M; compound III was the least potent in vitro and in vivo. Lengthening of the N-SAC of PHY markedly extended the duration of anti-AChE activity when compared to PHY, but rendered the modified compounds ineffective as pretreatments against soman. These data support the premise that the decrease in decarbamylation rates observed upon extending the N-SAC of PHY is responsible for the loss of effectiveness of pretreatment regimens against soman. Perhaps, these homologs of PHY may have potential use in instances where sustained action of acetylcholine is required at cholinergic junctions because of disease conditions or drug overdosage.

Acetylcholinesterase↗

PubMed1992

Effects of cholinergic and adrenergic agonists on adenylate cyclase activity of retinal microvascular pericytes in culture.

Pericytes are contractile cells that might help regulate microvascular blood flow. To understand their potential role in the regulatory responses of the retina and optic nerve head vessels, the response of pericytes isolated from bovine retinal microvessels was determined to oxotremorine, isoproterenol, phenylephrine, and clonidine. Isoproterenol doubled the basal levels of cyclic adenosine monophosphate (cAMP) specifically through beta-adrenergic receptors, because the effect was blocked by dl-propranolol. The alpha 1 agonist phenylephrine did not induce any major change in adenylate cyclase activity. The alpha 2 agonist clonidine decreased basal cAMP synthesis and reduced the effect of isoproterenol. The cholinergic agonist oxotremorine did not modify the basal activity of adenylate cyclase but was able to decrease by almost 50% the forskolin-induced increase of cAMP. These results suggest that pericytes have functional adrenergic and cholinergic receptors, and they might respond to autonomic vasoactive substances present in vivo.

Adenylyl Cyclases↗

PubMed1991

Rapid anticoagulation using ancrod for heparin-induced thrombocytopenia.

In order to determine the efficacy and safety of ancrod, a rapid acting defibrinogenating drug, for patients with heparin-induced thrombocytopenia, 11 consecutive patients who required anticoagulant therapy because of venous thromboembolism and who developed acute heparin-induced thrombocytopenia or had a history of heparin-induced thrombocytopenia were treated with ancrod. Heparin therapy was discontinued (in patients receiving heparin) and ancrod started at a dose of 1 to 2 U/kg every 24 hours with subsequent daily doses adjusted to maintain fibrinogen levels between 0.5 and 1.0 g/L. Ancrod was continued until warfarin had become effective. The platelet count increased to more than 150 x 10(9)/L within 2 to 10 days in all thrombocytopenic patients. Two patients with a history of heparin-induced thrombocytopenia maintained normal platelet counts while receiving ancrod. Two patients had recurrent venous thrombosis while receiving warfarin, 10 days after ancrod was discontinued: one of these patients had metastatic pancreatic carcinoma and developed phlegmasia cerulea dolens and the other patient developed a venographically proven extension of her deep venous thrombosis. One patient suffered a bleeding episode into the thigh with a 16-g/L decrease in her hemoglobin level while receiving ancrod therapy. No other side effects were noted. Our experience indicates that ancrod therapy is a reasonable approach for patients with heparin-induced thrombocytopenia who require anticoagulant therapy.

Aged↗

PubMed1991

The physiologic characteristics of relative pupillary block.

In biometric photographs of 13 patients, we quantified the iris contour in eyes with central anterior chamber depths ranging from 1.9 to 3.4 mm (epithelium to lens surface). This actual profile was compared to that predicted by a theoretical analysis of the forces acting on the iris. The average discrepancy between the calculated actual and the theoretically predicted iris position was only -0.01 to +0.03 mm. The close agreement validates the model under normal conditions and in the presence of relative (nonsynechial) pupillary block. The theoretical iris shape may not occur under conditions that violate the underlying physical assumptions of the mathematical model, such as when iridectomy eliminates the pressure difference between the anterior and posterior chamber or when synechiae introduce additional forces on the iris other than the ones included in the analysis.

Anterior Chamber↗

PubMed1991

Subcutaneous heparin therapy during pregnancy: a need for concern at the time of delivery.

Subcutaneous heparin is the treatment of choice for women requiring anticoagulant therapy during pregnancy. However, heparin therapy presents a management problem at delivery because of its potential to cause a persistent anticoagulant effect and thus increase the risk of bleeding. In order to avoid therapeutic complications it has been our practice to have women either discontinue their heparin injections with the onset of labour or to terminate heparin injections 12 h prior to elective induction. To determine the safety of our anticoagulant protocol at delivery we reviewed consecutive patients treated with subcutaneous heparin therapy during pregnancy, at our centre. Over a 23 month period we found that six of 11 women receiving subcutaneous heparin during pregnancy delivered while their aPTT was prolonged. In addition, three women received intravenous protamine sulphate prior to delivery and in one patient major bleeding occurred during an emergency cesarean section. Those women who had elevated aPTTs at the time of delivery all gave birth within 28 h of their last injection of heparin. In order to avoid a prolonged aPTT at delivery, we have now adopted a more conservative approach to the management of subcutaneous heparin use at term. Subcutaneous heparin is discontinued 24 h prior to commencing an elective induction of labour.

Female↗

PubMed1991

Abnormal scleral collagen in nanophthalmos. An ultrastructural study.

Ten patients with bilateral nanophthalmos underwent sclerectomies for uveal effusion. Ultrastructural examination of the sclera revealed abnormal collagen in seven patients. Four showed dramatic fraying of the collagen fibrils into fine filaments 2 to 3 nm in diameter. In three of these cases and three other cases without fraying, there were foci of 10- to 35-nm small collagen fibrils, some appearing to arise by splitting of otherwise normal collagen fibrils. In areas of fraying, elastic fibers were absent. All patients had a wider range of collagen diameters than did control subjects. The youngest patient with fraying also had Hallermann-Streiff syndrome. In three patients, no collagen abnormality was found. The clinical feature correlating best with the presence of abnormal collagen was an extremely small eye, since the three patients without collagen abnormality had the largest eyes (range of anteroposterior diameters, 19.2 to 20.3 mm). Nanophthalmos appears to result from several distinct defects.

Adult↗

PubMed1991

Comparison of analytic algorithms for detecting glaucomatous visual field loss.

The sensitivity and specificity of alternate analytic strategies for recognizing glaucomatous visual field loss from automated threshold perimetry (C-30-2 test of the Humphrey Field Analyzer) were compared among one eye each of 106 patients with glaucoma and 249 normal subjects. Algorithms included commercially available global indexes and cross-meridional differences (Statpac 1 and Statpac 2), as well as cross-meridional and cluster analyses that were developed independently for natural history studies and clinical trials. The sensitivity of most algorithms was high, except for those that used only diffuse loss as an indicator of abnormality. Specificity was acceptably high for all algorithms. Subjects who failed to meet the manufacturer's standard for reliability had much reduced specificity, but sensitivity was also affected. Algorithms that were based on any of the alternate definitions of localized reduction in retinal sensitivity performed equally well, which suggests that any of these approaches is useful in searching for glaucomatous visual loss as typified by this database. Availability, familiarity, and convenience may govern the selection of any one analytic approach for use in a particular setting.

Algorithms↗

PubMed1991

Statpac 2 glaucoma change probability.

We compared the traditional intuitive criterion (fixed at 5 dB) with the variable Statpac 2 criterion of the Humphrey Field Analyzer for identifying visual deterioration at individual points within a visual field. The separation of depressed from stable points in 123 follow-up fields of 17 patients, when all points within a field were considered, was reasonably equivalent between the two methods (kappa = 0.55 +/- 0.027 [+/- SE]). Centrally located points within the field demonstrated a stronger agreement (kappa = 0.68 +/- 0.028), because the fixed criterion more often labeled the edge points as having progressed than did the Statpac 2 algorithm. The glaucoma change probability printout is more simply obtained than the manual comparison required for intuitive interpretation with a fixed criterion, and it is potentially more accurate because of its reliance on a database that permits a variable criterion to be applied.

Aged↗

PubMed1991

Viscoelastic shear properties of the equine medial meniscus.

Recent studies have shown that the meniscus is highly anisotropic in tension and that its compressive creep behavior can be modeled using biphasic theory. In this study, an alternative approach is used, where viscoelastic shear properties of the meniscal fibrocartilage are measured to determine the anisotropy and inhomogeneity of this tissue with respect to specimen location and fiber orientation. Medial menisci were obtained from eight skeletally-mature horses. Nine test specimens were taken from the circumferential midsubstance of each meniscus, at three circumferential and three axial positions. The magnitude of the complex shear modulus and the phase angle were determined for each specimen from 100-800 Hz, in 100 Hz increments. Data were gathered shearing parallel and perpendicular to the circumferentially-oriented fibers. The magnitude of the shear modulus and the phase angle were both found to be frequency dependent, anisotropic, and inhomogeneous. The magnitude of the shear modulus increased with frequency, and was greatest in specimens from the posterior superior region, shearing parallel to the fibers. The phase angle decreased slightly with frequency and was lowest in specimens from the midsubstance of the anterior region, shearing perpendicular to the fibers. Our data demonstrated that collagen fibers substantially stiffen the meniscus in the direction of its fibers and that the solid matrix of the meniscus, like articular cartilage, behaves largely as an elastic material.

Animals↗

PubMed1991

The effect of test methodology on apparent compressive stiffness of tibiofemoral joint specimens.

Several investigators have analysed the compressive load bearing properties of the knee. Careful review of these force/displacement data showed considerable variation, with some investigators reporting displacements 12-15 x higher than others for nearly identical testing conditions using the same animal model. In this study, we sought to determine if this variability was inherent in the tibiofemoral joint or if differences in experimental methodology explained the variation. Compressive force/displacement curves were obtained from 39 normal canine tibiofemoral specimens mounted in a universal testing machine. Two commonly reported methods of measuring compressive displacement were used simultaneously. The testing machine crosshead displacement was used as one measure of displacement of the joint. The other method consisted of extensometers mounted to bone at the joint line. Resultant joint rotation in the parasagittal plane was also measured. Using either approach, we found comparatively little variation among the 39 specimens tested. However, the crosshead displacement measurements diverged from the extensometer measurements as the compressive load increased. At 770 N, the crosshead measurement was nearly twice the extensometer displacement. Further analysis showed that the compliances differed by a uniform amount. Parasagittal joint rotation, as measured by the extensometers, was minimal--less than one half of one degree. Although our loading fixtures were expected to be rigid under the loads used, these data suggest that the deformation of the bone and loading fixtures was responsible for the differences we observed, and may be responsible for the variation in compressive displacement results among several published studies. A model is presented which uses a simple elastic element to represent this deformation.

Animals↗

PubMed1991

Evaluation of phosphinates as potential pretreatments for nerve agents.

To assess the utility of phosphinates as pretreatments against nerve agents, experiments were conducted to determine whether oximes can reactivate phosphinate-inhibited guinea pig acetylcholinesterase (AChE) and whether the toxicity of phosphinates is reduced by treatment with atropine and/or oxime. Three phosphinates, 4-nitrophenyl methyl(phenyl) phosphinate (MPP), 4-nitrophenyl chloromethyl(phenyl) phosphinate (CMPP), and 4-nitrophenyl 2-methoxyphenyl(methyl) phosphinate (MPMP), were used in these experiments. In the first group of experiments, 2-PAM or HI-6 was administered, im, 2 min after peak inhibition of whole blood AChE activity by the phosphinates. Both oximes significantly reactivated MPP- or CMPP-inhibited AChE; however, HI-6 was the better reactivator in both cases. Oximes were ineffective against MPMP. Efficacy studies revealed that neither HI-6 nor 2-PAM potentiated the toxic effects of MPP or CMPP and that atropine/oxime therapy provided greater protection (up to 100 LD50s) against either phosphinate than any single therapy. The reactivation and efficacy data, especially for CMPP, support the concept that oxime sensitive phosphinates may be useful as pretreatments against nerve agent intoxication.

Acetylcholinesterase↗